In 2015, about 71,850 cases of non-Hodgkin lymphoma [NHL] will be diagnosed in the US. Approximately 35% of patients with NHL will present with indolent disease, which progresses very slowly, but is considered incurable. Because there is no survival benefit to initiating treatment immediately after diagnosis, a watch-and- wait [WW] approach (in which patients are monitored frequently) is the standard of care until disease-related symptoms emerge. The benefits of WW include reduced healthcare costs and avoidance of treatment-related side effects; however, many patients report elevated levels of distress and cancer-related worry during the WW phase. The uncertainty associated with the unknown trajectory of an incurable disease can be distressing and act as a powerful stressor, resulting in both psychological and physiological consequences. Notably, some individuals may be more affected by uncertain situations. Individual differences in various characteristics, such as intolerance of uncertainty [IU] and neuroticism, have been associated with greater stress and physiologic arousal. Over time, stress-related immune alterations may have clinical consequences for disease progression, since immune deficits are a strong risk factor for NHL. Natural killer [NK] cells, which are particularly sensitive to psychological stress, are critical i controlling NHL. In humans, lower numbers of NK cells, reduced viability of NK cells, and diminished expression of NK cell activating receptors have been associated with NHL disease progression and shorter survival, whereas stronger host immunity is associated with a more indolent disease course. T cells are also key effectors in mounting immune responses to NHL, and through the use of modern flow cytometry, their biomarker phenotypes can now provide sensitive indicators of immune function. Given the anxiety and distress associated with a WW approach, and the role of immune factors in disease progression, indolent NHL offers a unique disease model within which to examine biobehavioral pathways in an untreated cancer patient population. Thus, guided by a biobehavioral model of cancer stress, we propose to conduct a prospective, longitudinal study of 225 newly diagnosed patients with indolent NHL undergoing WW, to investigate whether poorer psychosocial functioning (as characterized by higher stress and anxiety) is associated with suppressed NK functional activity (degranulation response) and reduced expression of activating NK cell receptors, which in turn, have prognostic implications for disease progression over time. The specific aims are: Aim 1. To examine associations of psychosocial functioning (e.g., perceived stress, anxiety) with expression of NK cell and T cell activation markers and functional activity over time; Aim 2. To assess whether these immunologic markers are associated with a shorter interval of time to treatment; and Aim 3. To identify characteristics that may predict poorer outcomes over time. Study findings will have direct translational relevance, including a potential for early identification of patients at-risk or disease progression and the development of non-pharmacologic approaches for reducing morbidity in this understudied patient population.